Despite the use of effective antibiotics in combination with cardiopulmonary support, the mortality rate from sepsis and septic shock for the last three decades has remained high (2530% and 4070% respectively. Furthermore, the incidence of sepsis and septic shock appear to be increasing. Emerging data has suggested that activation of coagulation and suppression of fibrinolysis contributes to inflammation and vascular injury during sepsis. Based on this anticoagulants have been proposed for the treatment of deadly syndrome. Several new agents (human recombinant activated protein C, anti-thrombin III, tissue factor pathway inhibitor) that promote fibrinolysis or inhibit thrombin have not shown convincing benefit clinically and were frequently associated with increased risk of hemorrhage. However, these agents were not titrated based on any measure of anticoagulant effect (e.g. activated partial thromboplastin time, aPTT). Despite these negative findings, there has been continued interest in the use of heparin for sepsis. I one prospective study, heparin treatment was not associated with improved in survival while in another retrospective study it was. Importantly, different from prior anti-thrombotic aganets studied for sepsis, heparin treatment is titrated based on the aPTT. Based in part on this clinical experience, We further studied the effects of heparin in an E. coli challenged mouse model of pneumonia, both on measures of coagulation as well as on survival and lung injury. Experiments have now been completed for this study. The first part of the study investigated the effects of 3 heparin doses (100, 500, and 2500 u/kg, based on our prior studies and human dosing) or placebo on coagulation measures (PT, aPTT and TATc) over 4 h in normal animals. Dose 500 u/kg, a dose close to the one patients receive during 12 h of therapeutic heparin, increased aPTT levels into therapeutic ranges. The dose 2500 u/kg increased aPTT levels to supra-therapeutic levels. In the second part of the study, none of these three doses increased survival in animals challenged with intratracheal E. coli and the highest dose (2500 u/kg) worsened outcome. Of note, E. coli infection itself increased the aPTT compared to noninfected controls. These levels in infected animals aproached ones that would be considered therapeutic. Furthermore, heparin 100 u/kg produced therapeutic aPTT levels in infected but not noninfected animals, while heparin 500 u/kg was therapeutic in noninfected animals but supratherapeutic in infected animals. This higher heparin dose also increased early lung injury associated with intratracheal E. coli challenge. Overall these findings emphasize that use of anticoagulants in sepsis without monitoring parameters of coagulation may have unexpected effects. Most importantly, since infection can itself alter measures of anticoagulation, doses of antithrombotic agents necessary to achieve therapeutic aPTT levels in noninfected patients, may have to be reduced in those with infection. A manuscript is in preparation.